Pantothenic acid can be prepared by chemical synthesis, or biotechnologically by the fermentation of suitable microorganisms in suitable nutrient solutions. In the chemical synthesis, DL-pantolactone is an important compound. It is prepared in a multi-stage process from formaldehyde, isobutyraldehyde and cyanide. In further process steps, the racemic mixture is separated, D-pantolactone is subjected to a condensation reaction with .beta.-alanine, and D-pantothenic acid is obtained.
An advantage of the fermentative preparation by microorganisms is the direct formation of the desired stereoisomeric D-form.
Various types of bacteria, such as, for example, Escherichia coli, Arthrobacter ureafaciens, Corynebacterium erythrogenes, Brevibacterium ammoniagenes, and also yeasts, such as, for example, Debaromyces castellii, can produce D-pantothenic acid in a nutrient solution which comprises glucose, DL-pantoic acid and .beta.-alanine, as shown in EPA 0 493 060. EPA 0 493 060 furthermore shows that in the case of Escherichia coli, the formation of D-pantothenic acid is improved by amplification of pantothenic acid biosynthesis genes contained on the plasmids pFV3 and pFV5, in a nutrient solution comprising glucose, DL-pantoic acid and .beta.-alanine.
EPA 0 590 857 and U.S. Pat. No. 5,518,906 describe mutants derived from the Escherichia constrain IFO3547, such as FV5714, FV525, FV814, FV521, FV221, FV6051 and FV5069, which carry resistances to various antimetabolites, such as salicylic acid, .alpha.-ketobutyric acid, .beta.-hydroxyaspartic acid, O-methylthreonine and .alpha.-ketoisovaleric acid and produce pantoic acid in a nutrient solution comprising glucose, and D-pantothenic acid in a nutrient solution comprising glucose and .beta.-alanine. It is furthermore shown in EPA 0 590 857 and U.S. Pat. No. 5,518,906 that after amplification of the pantothenic acid biosynthesis genes contained on the plasmid pFV31 in the abovementioned strains, the production of D-pantoic acid in a nutrient solution comprising glucose and the production of D-pantothenic acid in a nutrient solution comprising glucose and .beta.-alanine is improved.
In addition, WO 97/10340 shows that in strains of Escherichia coli which form pantothenic acid, pantothenic acid production can be increased further by increasing the activity of the enzyme acetohydroxy acid synthase II, an enzyme of valine biosynthesis.